Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. Circulating PCSK9 binds to the low density lipoprotein receptor (LDLR) on the surface of hepatocytes and targets it for destruction. This process reduces the capacity of the liver to bind and remove LDL cholesterol (LDL-C) and thus results in increased LDL-C levels. Antibodies which specifically bind PCSK9 and block its interaction with the LDL receptor have been shown to be therapeutically useful for lowering serum LDL-C levels in human subjects. (See, e.g., Stein et al., New Engl. J. Med. 2012; 366:1108-1118).
The dosing amount and/or frequency of administration of an antibody necessary to produce a therapeutic effect is generally dictated by the number of antigens that can be neutralized by a single antibody molecule. For example, if an antibody can bind and neutralize only one antigen before the antibody is targeted for degradation within the host, then a relatively large amount of the antibody must be administered to produce a therapeutic effect and/or the antibody must be administered on a relatively frequent basis. On the other hand, if a single antibody is able to repeatedly bind multiple antigens before degradation, then less antibody needs to be administered, and can be administered on a less frequent basis, to result in an effective therapeutic response.
A need exists in the art for new therapeutic molecules capable of binding PCSK9 which can produce an effective therapeutic response for a longer period of time and/or with a lower dosing amount than what is required with currently known and available PCSK9 antagonists.